Movement Disorders Vol. 19, No. 7, 2004, pp. 807– 811 © 2004 Movement Disorder Society
Tumor Diagnosis Preceding Parkinson’s Disease: A Case–Control Study Marco D’Amelio, MD,1 Paolo Ragonese, MD,1 Letterio Morgante, MD,2 Antonio Epifanio, MD,2 Graziella Callari, MD,1 Giuseppe Salemi, MD,1 and Giovanni Savettieri, MD1* 1
Dipartimento di Neurologia, Ofthamologia, Otorinolaringoiatria, e Psichiatria, Universita` degli Studi di Palermo, Palermo, Italy 2 Dipartimento di Neurologia, Universita` degli Studi di Messina, Messina, Italy
Abstract: Lower cancer risk in Parkinson’s disease (PD) patients compared to the general population has been reported. However, most of the studies were based on death certificates. We designed a case– control study to estimate the association of tumor preceding PD onset and PD. PD patients were matched by age and gender to PD-free individuals, randomly selected from the municipalities of residence of cases. Occurrence of tumors preceding PD onset was assessed through a structured questionnaire. Neoplasms were categorized as benign, malignant, or of uncertain classification, and endocrine-related or not. Odds ratios (OR) were calculated using conditional logistic regression and adjusted for tumor categories and risk factors. We included 222 PD patients. Frequency of cancer was 6.8%
for cases, 12.6% for controls. PD patients had a decreased risk for neoplasms (adjusted OR, 0.4; 95% confidence interval [CI], 0.2– 0.7). Risk was reduced only for women (adjusted OR, 0.3; 95% CI, 0.1– 0.7). PD patients had a decreased risk both for malignant (adjusted OR, 0.6; 95% CI, 0.1–2.5) and nonmalignant neoplasms (adjusted OR, 0.3; 95% CI, 0.1– 0.7). Still, risk was decreased for endocrine-related tumors (adjusted OR, 0.3; 95% CI, 0.1– 0.9) and non– endocrine-related tumors (adjusted OR, 0.4; 95% CI, 0.1– 0.9). Our study confirms the inverse association between PD and neoplasms reported in previous epidemiologic studies. © 2004 Movement Disorder Society Key words: Parkinson’s disease; tumors; epidemiology; case– control
Several studies have investigated the association between Parkinson’s disease (PD) and cancer using different methods. Some authors estimated cancer frequency in PD patients through the analysis of causes of death,1,2 others by the analysis of a cancer registry of prevalent community-based cases,3 or more recently by a case– control study in an incident population-based cohort of PD patients.4 Most of these studies have been characterized by rather small population samples and, in the case of mortality studies, by inaccuracy of the results related to the use of death certificates as source of information. Moreover, benign tumors have been excluded from data col-
lection and only two studies, to our knowledge, determined tumors occurrence among PD individuals including risk factors for PD and neoplasms.4,5 There are several explanations why PD could be inversely associated with neoplasms. Caspase’s cascade and the ubiquitin proteasome pathway are involved in apoptosis,6,7 and it is likely that they play a role both in the development of PD and in that of cancer. On these bases, we conducted a case– control study in a clinical series of PD individuals from two neurological departments. PATIENTS AND METHODS Cases and Controls Patients with idiopathic PD were consecutively recruited outpatients from the neurological clinics of Palermo and Messina, starting February 2001 to May 2002. The same diagnostic criteria used in a population-based survey on the prevalence of PD in Sicily were applied.8 In brief, idiopathic PD diagnosis was based on the presence of two of four cardinal signs in people who were not on antiparkinsonian therapy: tremor at rest, rigidity, bra-
*Correspondence to: Dr. Giovanni Savettieri, Dipartmento di Neurologia, Ofthamologia, Otolaringoiatria, e Psichiatria, Universita` degli Studi di Palermo, via Gaetano La Loggia 1, 90129 Palermo, Italy. E-mail
[email protected] Received 17 June 2003; Revised 9 January 2004; Accepted 6 February 2004 Published online 21 April 2004 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.20123
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dykinesia, and impaired postural reflexes; at least one of the above-mentioned signs was required in individuals who were taking antiparkinsonian therapy. Diagnosis was supported by unilateral onset, progressive course, asymmetry of signs, and good responsiveness to antiparkinsonian drugs (levodopa or dopamine agonists). Vascular and other forms of parkinsonism were excluded through a screening for history of stroke, head trauma, encephalitis, and sudden onset or stepwise progression of symptoms. Individuals who were on neuroleptic drugs in the 6 months before the onset of symptoms or who showed the presence of cognitive impairment or of other neurological signs within the first year of onset were also excluded. Brain computed tomography, magnetic resonance imaging, or single-photon emission tomography, although not critical for the inclusion, were also evaluated when available. PD onset was defined as the year in which one of the cardinal signs was first noted. PD patients were matched (1:1) by gender and age (⫾ 2 years) to individuals free of neurological diseases randomly selected from the population records of the municipality of residence of the case. Diagnoses were reviewed by at least 2 neurologists at each Neurological department where cases and controls were identified. The same neurologists, through an extensive review of medical history and a careful neurological examination, ascertained the absence of neurological diseases in controls. Both cases and controls were screened for cognitive impairment by Mini-Mental State Examination (MMSE); those individuals scoring less than 24 were excluded. Risk Factor Assessment Frequency of neoplasms, preceding onset of PD symptoms for patients and before the index year for controls, was assessed through a structured questionnaire administered to each case or control by trained personnel. Information reported by individuals on the localization and grading of the neoplasms were confirmed through the review of medical records, when available (⬃80%). Both cases and controls were asked if they had ever been diagnosed with any of the following diagnoses: cancer, neoplasms, tumors, cyst, or nodule. Information regarding tumors (malignant/nonmalignant, localization, endocrine system relationship) and risk factors (alcohol, coffee, smoking habit) was also collected. We considered endocrine-related neoplasms, those affecting the endocrine system (i.e., endocrine pancreas, parathyroid, pheochromocytoma, pituitary gland, thyroid), and those for which a hormonal influence has been demonstrated (breast cancer, corpus of the uterus, prostate).
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Subjects were classified as nonsmokers (less than an average of a pack of cigarettes per month during their adult life) and smokers (at least an average of a pack of cigarettes per month during their adult life). Alcohol consumption was classified as nondrinkers (less than an average of a glass of alcohol per week during their adult life) versus drinkers (at least an average of a glass of alcohol per week during their adult life). Similarly coffee consumption was categorized as never (less than a cup of coffee per week during their adult life) versus ever (at least a cup of coffee per week during their adult life). Data Analysis A case– control matched pair design was used. Relative risk in PD patients was estimated by the calculation of the odds ratio (OR) and adjusted for smoking habit and alcohol and coffee consumption by conditional logistic regression analysis. To evaluate the effect of smoking, we performed an analysis where the association between PD and neoplasms was estimated separately in the smokers and nonsmokers. RESULTS Three hundred sixty-eight individuals complaining of parkinsonian signs were visited in the two centers during the study period. One hundred ten subjects (29.9%) did not meet the criteria used in the study for a diagnosis of idiopathic PD and were subsequently excluded. Of the remaining 258 subjects, 25 (9.7%) scored less than 24 on the MMSE. Among PD individuals, only 11 subjects refused to participate in the study (response rate 95%). Finally, 222 PD patients (127 women, 95 men) and 222 matched controls were included in the study. Response rate was high also among controls (92%). PD patients had a median age at interview of 67.7 years. Because of the matching, the age and sex distributions were similar in controls. Median age at PD onset was 61 years and median PD duration 6.0 years. We did not observe a significant difference between men and women for these variables (see Table 1). Education level, taken as completed years of education, was stratified in four groups: 0 years, 1 to 8 years, 9 to 13 years, more than 13 years. Occupational status was coded in four different categories as follows: housewives, manual workers (including factory workers, handicraftsmen, farmers, other manual works), intellectual workers (including clerks, salesmen, and professionals), all others. No difference between cases and controls, estimated by chi-squared analysis, has been observed for these variables (see Table 2). Neoplasm diagnoses preceding PD were reported by 15 PD patients (6.8%; 4 men; 11 women) and 28 controls (12.6%; 4 men; 24 women; P ⫽ 0.001; Table 3). Median
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TABLE 1. Characteristics of PD individuals All individuals
Age at interview (yr) Age at PD onset (yr) PD duration (yr)
Males
Females
Mean
Median
Min
Max
Mean
Median
Min
Max
Mean
Median
Min
Max
65.8 59.5 6.3
67.7 61.0 6.0
32.9 31.0 0.1
85.1 81.0 22.0
67.4 59.9 6.0
67.9 61.0 6.0
32.9 31.0 0.1
85.1 78.0 19.0
66.0 58.8 6.5
67.6 61.0 6.0
43.2 33.0 0.1
84.5 81.0 22.0
PD, Perkinson’s disease.
age at tumor diagnosis was 48 years among cases and 52 years among controls (P ⫽ 0.7). Multivariate analysis showed an inverse association between PD and tumor (adjusted OR, 0.3; 95% confidence interval [CI], 0.2– 0.7; P ⫽ 0.004). The association was statistically significant only for women (adjusted OR, 0.3; 95% CI, 0.1– 0.7), whereas it was not observed for men (adjusted OR, 0.9; 95% CI, 0.2–3.9). Both nonmalignant (adjusted OR, 0.3; 95% CI, 0.1– 0.7) and malignant neoplasms (adjusted OR, 0.5; 95% CI, 0.1– 2.5) were less frequently reported by PD individuals compared to controls (Table 3). Similar results were observed for endocrine- and non– endocrine-related tumors (Table 3). When compared to controls, PD patients showed a decreased risk both for non– endocrine-related neoplasms (adjusted OR, 0.4; 95% CI, 0.1– 0.9) and endocrine-related neoplasms (adjusted OR, 0.3; 95% CI, 0.1– 0.9). Tumor frequencies by site is shown in Table 4. Among women, 54.6% of cases and 62.5% of controls reported a tumor of the uterus. This tumor was significantly inversely associated with PD (adjusted OR, 0.5; 95% CI, 0.3– 0.9). When tumors of the uterus were excluded from the analysis, the association, although present, did not reach the statistical significance (adjusted OR, 0.4; 95% CI, 0.1–1.3). Two cases and one control, reporting more than one tumor with different localization, were analyzed as if they had only one neoplasm. TABLE 2. Frequency distribution of years of education and occupation among cases and controls Cases
Controls
5 (2.3) 164 (73.9) 35 (15.8) 18 (8.0)
2 (0.9) 149 (67.1) 46 (20.7) 25 (11.3)
76 (34.2) 67 (30.2) 76 (34.2) 3 (1.4)
72 (32.4) 86 (38.7) 61 (27.5) 3 (1.4)
a
Education (yr) 0 1–8 9–13 ⬎13 Occupationb Housewives Manual workers Intellectual workers All others a
P ⫽ 0.2; df ⫽ 3; 2 ⫽ 4.64. P ⫽ 0.2; df ⫽ 3; 2 ⫽ 4.11.
b
Tumor occurrence was also estimated stratifying cases and controls by smoking habit (never vs. ever) by Mantel–Haenszel analysis (Table 5). We found that neoplasms were constantly decreased among cases compared to controls both in the smokers (OR, 0.4; 95% CI, 0.1–1.6) and in the nonsmokers (OR, 0.5; 95% CI, 0.2– 1.2; Breslow-Day test for homogeneity P ⫽ 0.8; chisquared ⫽ 0.0473, DF ⫽ 1). Similar analysis has been performed for the other risk factors (alcohol and coffee use). The inverse association between PD and tumors was confirmed also after stratifying for these variables. Considering the higher frequency of neoplasms of the uterus among controls, we also looked at the use of premenopausal estrogens. Although based on small numbers (only 9 cases and 10 controls ever used exogenous estrogens), we did not observe any significant difference between cases and controls for this variable (P ⫽ 0.8). DISCUSSION In this case– control study, we confirm previous findings of lower tumor rates among PD patients. This relationship, however, seems to be gender-specific. Our study is the first evaluating the frequency of nonmalignant neoplasms among PD individuals. In our series, both malignant and nonmalignant neoplasms were less represented among cases compared to controls; however, only nonmalignant tumors were significantly reduced. The lack of significance for malignant cancer may be attributable to the small number for these types of tumors in our series. Our results suggest that negative results of previous studies might be ascribed to the exclusion of nonfatal tumors. Because of the low rate of neoplasms in the whole cohort, we cannot infer any relationship regarding hormonal factors (endocrine relationship of neoplasms) and the association of PD and tumors, especially about their localization. Strong epidemiological evidence indicates that smokers have a lower risk of Parkinson’s disease.9 It has been hypothesized that during their life, PD patients might have smoked less than individuals who did not develop PD. According to some authors, this finding would be the explanation why lower cancer rates (espe-
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M. D’AMELIO ET AL. TABLE 3. Association between Parkinson’s disease and nonfatal cancer preceding PD onset Variable
Tumor frequency No Yes Tumors by gender Males Females Tumor grading No neoplasm Non malignant Malignant Uncertain Tumor endocrine relationship No neoplasm Not endocrine related Endocrine related
Cases (%)
Controls (%)
OR (95% CI)
P
ORa (95% CI)
P
207 (93.2) 15 (6.8)
194 (87.4) 28 (12.6)
1.0 (Referent) 0.5 (0.3–1.0)
0.03
1.0 (Referent) 0.4 (0.2–0.7)
0.004
4 (4.2) 11 (8.7)
4 (4.2) 24 (18.9)
1.0 (0.2–4.1) 0.4 (0.2–0.9)
1.0 0.02
0.9 (0.2–3.9) 0.3 (0.1–0.7)
0.9 0.004
207 10 (66.7) 3 (20) 2 (13.3)
194 20 (71.0) 6 (21.4) 2 (7.2)
1.0 (Referent) 0.5 (0.2–1.0) 0.5 (0.1–1.9) 0.9 (0.1–6.7)
0.06 0.3 0.9
1.0 (Referent) 0.3 (0.1–0.7) 0.5 (0.1–2.1) 0.4 (0.1–3.5)
0.006 0.4 0.4
207 8 (53.3) 7 (46.7)
194 14 (50.0) 14 (50.0)
1.0 (Referent) 0.5 (0.2–1.3) 0.5 (0.2–1.2)
0.2 0.1
1.0 (Referent) 0.4 (0.1–1.0) 0.3 (0.1–0.9)
0.05 0.02
ORa, odd ratio adjusted for smoking habit and alcohol and coffee consumption; PD, Parkinson’s disease; CI, confidence interval.
cially smoking-related cancer) among PD individuals would have been observed.10 Smoking habit alone, however, cannot explain the inverse association between PD and cancer. In fact, we observed a decreased tumor frequency in PD individuals whether they smoked or not. Biological plausibility of our findings comes from accumulating evidence suggesting that apoptosis is involved in dopaminergic cell death in Parkinson’s disease and in related in vitro and animal models.11 Moreover, accumulating data suggest that defects in apoptosis signaling are a prerequisite for cancer.12 Caspase’s cascade, the central engine of apoptosis, could be the key to understanding why PD individuals might be somehow protected from cancer. However, according to this hypothesis, the effect would not be cancer- and genderspecific. Other factors might be implicated. Derangements in the ubiquitin-dependent proteolysis, might contribute to the observed inverse association. The ubiquitin proteasome pathway (UPP) is in fact critical in the degradation of proteins involved in cell cycle control and TABLE 4. Distribution of neoplasms by site Cancer site
Cases
Controls
Ovary Uterus Breast Skin CNS Prostate Intestine Others More than one sitea Total
1 5 2 0 1 1 1 2 2 15
2 14 1 1 1 1 3 4 1 28
a
Neoplasms reported in this strata were breast/skin and uterus/intestine for cases and breast/uterus for the control. CNS, central nervous system.
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growth tumor.13 For example, the p53 protein, a tumor suppressor protein mutated in over 50% of cancers, is degraded by the UPP.14 Alterations or reductions in ubiquitin-mediated proteasome function is associated with some forms of parkinsonism, and multiple lines of evidence suggest that this mechanism of protein degradation may play an important role in the etiology of PD.15 A recent study reported an interaction of UPP-related genes (␣-synuclein and ubiquitin carboxy-terminal hydrolase L1) and PD only in women.16 It is reasonable that PD in women, more often than in men, results from a genetic disruption of the UPP, thus leading to a reduced cancer risk. By contrast, men might more often develop PD by means of exogenous mechanisms, independent of genetic disruption and the UPP, explaining the lack of the inverse association with cancer. Our study has limitations. PD individuals have been identified from prevalent cases of two neurological departments. Similar sex-specific prevalence figures of PD in Sicily have been reported.8 In addition, individuals with cognitive impairment, which is more common in men than in women, have been excluded from the TABLE 5. Mantel–Haenzel analysis: risk of neoplasm among smokers and nonsmokers Smoking habit Nonsmokers Cancer no Cancer yes Smokers Cancer no Cancer yes
Cases (%)
Controls (%)
OR
95% CI
126 (91.3) 12 (8.7)
104 (83.9) 20 (16.1)
Referent 0.5
0.2–1.1
81 (96.4) 3 (3.6)
90 (91.8) 8 (8.2)
Referent 0.4
0.1–1.6
OR, odds ratio; CI, confidence interval.
TUMOURS PRECEDING PARKINSON’S DISEASE study.17 These data explain the inclusion of higher proportion of women compared to men. Recall bias is one of the most common and subtle risks of retrospective studies. However, a high level of agreement between selfreported medical history and data abstracted from medical records has been demonstrated.18 –21 Moreover, as suggested by Sackett,22 individuals with a chronic disorder, such as PD patients, tend to report other diseases more frequently than controls. They also may come to medical attention more often and be diagnosed once they have the disease. The results of our study, although based on clinical series, are strengthened by several issues. First, as remarked by others,4 most of the studies not based on death certificates performed in recent years were characterized by a not-validated PD diagnosis. Second, the case– control matching (by gender, year of birth, and municipality of residence) reduced the chance to observe differences due to a different temporal and spatial cancer occurrence between the two groups. Of the two case– control studies, with sample sizes large enough to estimate a significant association between cancer overall and PD,4,23 only one4 was not based on death certificates. Finally, we collected information regarding cancer risk factors. These data to our knowledge have been reported only by two other studies.4,5 Our results are similar to the study conducted in Rochester, Minnesota.4 Major difference in the results consists of lower cancer rates observed in our study. This result might be attributable to higher cancer frequencies in North America compared to Southern Europe.24 Acknowledgments: We thank Dr. Karen Marder, G.H. Sergievksy Center, College of Physicians and Surgeons, Columbia University, New York, NY, for her help and suggestions. This work was supported by a grant of the Italian Ministry of University and Research (MIUR), for the year 2000.
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